The recent submission by Alshehri et al[1] highlights the current evidence supporting the treatment of oligometastatic disease (OMD) from different primary cancers and practical considerations for definitive treatment. We congratulate the authors for this extensive review and their systematic approach in summarizing the data. We believe that one of the greatest current controversies is how to best identify patients who would benefit from OMD-directed treatment—in other words, to recognize those patients who are truly oligometastatic. Previous and ongoing studies identify OMD mostly by the number of metastatic sites involved as the main indicator of eligibility.[2] Data evaluating tumor and metastatic site microenvironment and genetic makeup are evolving, and conventional imaging should be ultimately considered a crude marker of the oligometastatic state.[3] Furthermore, the current definition of OMD, which is set at an arbitrary three to five sites of disease, is unfortunately informed more by technical considerations than by biological rationale. Thus, a biologically driven definition of oligometastatic disease is urgently needed, and we think two of the most promising avenues to arrive at such a definition are molecular imaging and circulating bioanalytics.

Although tumor- and metastasis-directed biopsies reveal the histopathology and disease microenvironment, certain types of malignancies have unique bioanalytical marker(s) that can be evaluated within the peripheral blood. Serum prostate-specific antigen is an example for prostate cancer, whose level has been used to stratify patients' risk groups, guide therapy decision-making, and as a surveillance tool to assess treatment response. A similar marker indicative of minimal residual disease is needed in other tumor types. To this end, circulating tumor cells, tumor RNA, exosomes, and tumor DNA are being evaluated in different malignancy types.[4] These allow disease burden and treatment response to be accurately monitored, which might help identify patients who would benefit the most from local therapy of OMD disease.

OMD and oligometastatic recurrence detection by advanced, targeted cancer-specific molecular imaging has shown superior sensitivity as compared to conventional imaging modalities. Nowhere is this more evident than in prostate cancer where increasingly we are identifying OMD in patients previously thought to have biochemical recurrence and or high-risk disease. This trend was recently highlighted in an article by Calais et al,[5] who found that gallium–prostate-specific membrane antigen PET-CT showed higher detection rates of oligometastatic recurrence in patients with otherwise biochemical-limited disease than did F18-fluciclovine PET-CT, identifying eight patients with extrapelvic lesions who were otherwise negative by conventional imaging. Adopting similar imaging strategies to OMD from other cancer types would require identification of suitable molecular targets.

We would like to acknowledge the authors and re-emphasize the importance of OMD definition, treatment, and response measurement. We believe that the future for OMD treatment remains promising especially if the definition of this disease state is aided by biologically driven markers. Thus, there exists a significant need to develop trials that not only test the efficacy of OMD-directed therapy but also use extensive translational biomarkers, such as in our current EXTEND randomized phase II basket trial (NCT03599765).

References

References
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Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study
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Competing Interests

Source of Support: None. Conflict of Interest: Chad Tang received funding from the Cancer PRevention and Research Institute of Texas to fund the EXTEND trial. The other authors have nothing to disclose.